Opioid drugs are potent analgesics which exert their effects by activating opioid receptors within and/or outside the central nervous system. Opioid receptors have been demonstrated on sensory nerves in both inflamed and normal subcutaneous tissue.
It has been shown that when opioids are applied locally (i.e., intraplantarly) to circumscribed inflamed areas outside the central nervous system, they can produce analgesic effects by activating opioid receptors on peripheral sensory nerves. (Stein Eur. J. Pharm. 155:255-265 (1988); Stein et al., Neurosci. Lett., 84:225-228 (1988)). Importantly, such peripheral analgesic effects can be achieved with very low doses of opiates which do not reach the brain (i.e., do not cross the blood-brain barrier) and, therefore, do not produce the well known and serious central opioid side effects (e.g., somnolence, nausea, depression of breathing, dysphoria, addiction). This has been shown in a large number of controlled and published studies in animals (Stein et al., Neurosci. Lett., 84:225-228 (1988); Stein et al., Eur. J. Pharmacol., 155:255-264 (1988); Stein et al., J. Pharmacol. Exp. Ther., 248(3):1269-1275 (1989); Stein et al., Proc. Natl. Acad. Sci. USA, 87:5935-5939 (1990); and Stein et al., J. Neurosci., 10:1292-1298 (1990)) and in humans (Stein et al., New Engl. J. Med., 325:1123-1126 (1991); Khoury et al., Anesthesiology, 77:263-266 (1992); and Stein et al. Lancet, 342:321-324 (1993)).
A drawback to the widespread application of locally injected opioids for pain relief has been the fact that, although these peripheral analgesic effects may be elicited to some extent in inflamed tissue, these effects have not been elicited in non-inflamed tissue (C. Stein, Anesth. Anal., 76:182-191 (1993)). It is believed that one reason for this lack of opioid analgesic effect in non-inflamed tissue is the fact that opioid receptors on peripheral sensory nerves are not easily accessible due to a rather impermeable barrier sheath around those nerves, the so-called perineurium (Y. Olsson, Crit. Rev. Neurobiol., 5(3):265-311 (1990). This barrier is deficient in inflamed tissue and, therefore, the opioid receptors become easily accessible to opioid drugs under those circumstances. Therefore, it is important to find an analgesic, that when locally applied to normal tissue will elicit pain relief without the serious central opioid side effects.
The endothelial blood vessels in the brain (the so-called blood brain barrier, "BBB") can be artificially disrupted by hyperosmolar solutions (Olsson, Crit. Rev. Neurobiol., 5(3):265-311 (1990)). Based on the known ultrastructural similarities between the perineurium and the BBB, the inventor performed experiments wherein such hyperosmolar solutions were injected into non-inflamed subcutaneous tissue of rats. The inventor found that these hyperosmolar solutions produced a leakage of the perineurium to analytes. This leakage was demonstrated by histochemical staining of peripheral nerves after subcutaneous injection of a marker substance (horseradish peroxidase) that normally does not easily penetrate into these nerves, but that did so after administration of hyperosmolar solutions. Further, mannitol and other hyperosmolar solutions, by themselves, are devoid of analgesic actions and (at the concentrations necessary to enhance local analgesic effects) are nontoxic in peripheral tissues.
Thus the inventor determined that the administration of extremely small, systemically inactive doses of opioids, opioid peptides (derivatives of the naturally occurring endorphins) or other local anesthetics result in a potent enhancement of the analgesic effects after local application in non-inflamed tissue when delivered in a hyperosmolar solution.